Synthesized gamma-carbolines

ABSTRACT

The present invention concerns the compounds of the formula:  
                 
and the prodrug and salts thereof, wherein R may be a hydroxyl or other pendent group and Ar is an aryl. The compositions may be adapted for the treatment of neurodegenerative diseases. Further, the compositions may be adapted as a pharmaceutical such as an antipsychotic pharmaceutical, an antibiotic pharmaceutical, an antiviral pharmaceutical or an antitumor pharmaceutical.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of provisional patentapplication Ser. No. 60/448,910 to Wynne et al., filed on Feb. 24, 2003,entitled “Synthesized γ-Carbolines,” which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The present invention relates to novel synthesis of γ-carbolines. Morespecifically, the present invention provides for synthesis offunctionalized γ-carboline derivatives.

β-Carbolines, pyrido[3,4-b]indoles, are of interest to thepharmaceutical industry due to their close relationship with naturalproducts such as tryptophan as well as their numerous reportedbiological activities. Through the years, a number of reports have shownthat γ-carbolines, pyrido[4,3-b]indoles, also possess similar biologicalactivities. Several substituted γ-carbolines have been synthesized andexamined in a series of in vitro and in vivo pharmacological tests andhave demonstrated antipsychotic, antibiotic, antitumor and other relatedactivities.

There exists no general efficient synthetic route that allows for theformation of highly functionalized γ-carbolines, especially those thatcontain substituents in the 1- and 4-positions. Of the methods reported,the most widely used for y-carboline formation is the Fischer synthesis,which often fails completely, or proceeds in low yields unless forcingthermal conditions are used or an activated pyridine ring is employed.An alternative approach is the Grabe-Ullman synthesis and subsequentmodifications. This reaction involves the preparation of thephenyl-substituted triazolopyridine followed by elimination of nitrogenupon thermal degradation at temperatures ranging between 190° C. and500° C. Microwave irradiation has also proven successful on severalsubstrates. Likewise, the formation of a small series of γ-carbolineshas been reported by the ring closure of internally generated2-nitrosobiphenyls synthesized in situ. This reaction proceeds inmoderate yields; however, the products are limited to alkyl substitutedcarbolines. Many of these previously reported methods requiringintramolecular cyclization, proceed in low yields, are limited tonon-functional substrates, or involve extreme thermal conditions.

The formation of the desired γ-carbolines in several cases, werebyproducts formed while attempting to synthesize the more notableβ-carbolines. A unique three-step γ-carboline synthesis employing4-chloropyridine and o-phenylenediamine in a catalytic palladium (II)coupling reaction was developed while two researchers, Robinson andThomley, were attempting to synthesize β-carbolines.

Likewise, the intramolecular coupling of a boronic acid witho-fluoroiodopyridine by a Suzuki-type reaction employing a Pd (0)species has been reported. Although an efficient conversion, it involvesthe synthesis of specialty starting materials, and examples are few innumber. The authors reported that the overall three-step process islimited to non-acid-sensitive substrates.

More recently, a novel palladium-catalyzed iminoannulation of internalalkynes was developed. This unique method allows the introduction offunctionality into both the 3- and 4-positions of γ-carbolines.Additionally, Larock's group has shown that 3-substituted γ-carbolines,some of which possess 4-annularization, are readily available by a novelpalladium/copper catalyzed cyclization reaction of intramolecular orterminal alkynyl indoles. These products have been compared tocarbolines which act as cardiovascular agents or as 5-HT₃ receptorantagonists. Because of these recent advances and the importance of thisclass of compounds, needed is a general synthesis and novel approach toafford the complimentary series of 7-carbolines that are substituted inthe 1- and 4-positions.

One possible precursor to β-carbolines is through the correspondingtetrahydro-β-carboline and subsequent derivatives. Molecules of thisclass have recently shown potential for multi drug resistance. The mostnoted method of synthesis of such proceeds via the Pictet-Spenglersynthesis, which condenses triptamine, a 3-aniinomethylindole, with avariety of aldehydes. A simple method to afford the isomeric substitutedtetrahydro-γ-carbolines is lacking even though these compounds are alsopredicted to exhibit multidrug resistance.

The lack of commercially available 3-aminomethyl indoles, or the facilesynthesis of these has hindered the synthesis of the correspondingγ-carbolines. This provides an additional driving force for thedevelopment of a method to afford a large selection of functionalizedγ-carbolines. A methodology is desirable which allows ease in control ofsubstituents, especially in the 1-position and 4-position, thus creatingcompounds likely to exhibit desirable pharmacological and biologicaleffects.

BRIEF SUMMARY OF THE INVENTION

One advantage of the present invention is that it provides for thegeneration of compounds that may easily be manipulated to achieve usefulphannacologicallbiological effects.

Another advantage of this invention is that it provides for thesynthesis of γ-carbolines without a need for specialty startingmaterials.

A further advantage of this invention is that it provides for thesynthesis of tetrahydro-γ-carbolines.

Yet a further advantage of this invention is that it provides a generalsynthetic methodology that allows for ease in control of substituents,not only in the 1-position, but also in the 4-position.

Yet a further advantage of this invention is that it provides a generalsynthetic methodology that does not require extreme thermal reactionconditions.

To achieve the foregoing and other advantages, in accordance with all ofthe invention as embodied and broadly described herein, are compounds ofthe formula:

and the prodrug and salts thereof and reported precursors thereto,wherein R may be a hydroxy, alkoxy, acyl, alkyl, alkenyl, aryl group oreven a hydrogen. The Ar in position 1 may be any aryl or substitutedaryl group.

In yet a further aspect of the invention, are compounds of the formula:

and the prodrug and salts thereof and reported precursors thereto,wherein R1 may be a tosyl, a hydrogen, or any other sulfonate group andR2 may be a hydrogen, TBDMS, or any other sterically hindered silylgroup. The Ar in position 1 may be any aryl or substituted aryl group.

In yet a further aspect of the invention, these compounds may be adaptedfor the treatment of neurodegenerative diseases. Further, thecompositions may be adapted as a pharmaceutical such as an antipsychoticpharmaceutical, an antibiotic pharmaceutical, an antiviralpharmaceutical or an antitumor pharmaceutical.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing or may be learned by practice of the invention. The objectsand advantages of the invention may be realized and attained by means ofthe instrumentalities and combinations particularly pointed out in theappended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The accompanying drawings, which are incorporated in and form a part ofthe specification, illustrate embodiments of the present invention and,together with the description, serve to explain the principles of theinvention.

FIG. 1 shows direct treatment of indole (1) using compounds (2) in arefluxing xylene process to preferably generate substituted products(3).

FIG. 2 shows treatment of 3-bromo-1-TBDMS indole (4) withtert-butyllithium followed by condensation with a variety ofN-tosylaldimines (2), which may produce 1-protected-3-arylaminomethylindoles (6).

FIG. 3 shows treatment of compound (6), with sodium ethoxide followed byaddition of ethyl bromoacetate, which may afford compound (7).

FIG. 4 shows two embodiments of creating a y-carboline molecule as perthe present invention.

FIG. 5 shows a process of creating the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for synthesis of functionalizedγ-carboline derivatives and their tetrahydro precursors. This synthesisalso allows for the production or the facile synthesis ofnon-commercially available 3-aminomethyl indoles. This method mayprovide a large selection of functionalized γ-carbolines by controllingthe substituents, not only in the 1-position, but also in the4-position.

The following descriptions describe preferred embodiments of practicingthe present invention. However, one skilled in the art will recognizethat many modifications may be made to these descriptions while stillobtaining the intended results.

Preferably, the present invention may start with readily availableindole and proceed by a method which allows for control of substituentsin the 1- and 4-positions in the final γ-carboline product, or itstetrahydro precursors.

Reagents may be obtained from commercial suppliers and may be usedwithout further purification. Melting points may not need to becorrected; FTIR spectra of samples may be obtained in numerous waysincluding KBr pellets or on NaCl disks. ¹H NMR and ¹³C NMR may bedetermined at frequencies such as 300 or 75 MHz in CDCl₃ or othersolvents. Chemical shifts may be reported downfield from TMS. Couplingconstants, J, are preferably reported in Hz. Elemental analysis may beperformed using a device such as a Perkin-Elmer Series II, C, H,N-Analyzer Model 2400 or at a commercial establishment such as AtlanticMicrolab, Inc. in Norcross, Ga. may be used for elemental analysis. TBFmay be distilled from sodium/benzophenone ketal-pair and CH₂Cl₂ fromP₂O₅, all under nitrogen. All moisture-sensitive reactions and reagenttransfers may be carried out through nitrogen or argon. Thin layerchromatography (“TLC”) may be performed on Eastman Kodak precoatedsilica gel sheets with glass backing. Preparative column chromatographymay be performed on an Isco-100s automated flash column chromatographsystem employing pre-packed silica gel columns 60 Å (200-400 mesh).

Treatment of indole (1) using compound (2) in a refluxing xylene processmay be used to generate substituted products (3), as shown in FIG. 1.For example, in compounds 2 and/or 3, Ar may be Ph, p-MeOPh, or p-CIPh.

The use of bulky silyl protecting groups may produce good yields whenintroducing various alkyl and organometallic substituents into the3-position of the indole ring. Rearrangement, as described above, may becircumvented through the use of either a tert-butyldimethylsilyl(“TBDMS”) or diisopropylsilyl (“TIPS”) or other bulky silyl protectinggroup. The 3-bromo-1-TBDMSindole (4) may be prepared using the proceduredescribed by Bosch and co-workers as documented in J. Org. Chem., 1994,59, 10-11.

FIG. 2 shows treatment of 3-bromo-1-TBDMS indole (4) withtert-butyllithium followed by condensation with a variety ofN-tosylaldimines (2). Other alkyl lithium reagents may also be used toafford the desired product. Such treatment may afford the corresponding1-protected-3-arylamninomethyl indoles (6) in good yields. Thisprocedure may allow for a wide variety of aryl substituents containingboth electron withdrawing and electron donating functionalities to beintroduced. The aryl substituent on tosylaldimine (2) will likely becomethe 1-position aryl group of the final γ-carboline molecule. Alteringthe tosylaldimines (2) should allow for direct control of thesubstituent in the 1-position of the final γ-carboline molecule.

Subsequently, treatment of 1-protected-3-arylaminomethyl indoles (6),with sodium ethoxide followed by addition of ethyl bromoacetate, mayafford compound (7). A variety of bases may be employed such as sodiumhydroxide, sodium hydride, potassium hydroxide, sodium methoxide,potassium methoxide or alkyl lithiums.

FIG. 4 shows the treatment of compound (7) with a variety of Lewisacids, which may afford the desired 1,2-dihydro-3-H-γ-carbolone (8), atetrahydro-γ-carboline, upon intramolecular cyclization. The desiredcarbolone (8) may afford lower yields than expected, due tocontamination with compounds (9), (10) or (11). A variety of Lewis acidssuch as BF3*Et₂O, PPA, ZnCl₂, AlCl₃, TiCl₄, Bentonite K-10 Clay andP₂O₅, may be cyclizing catalysts. Bentonite K-10 Clay may yield thehighest result. Stronger Lewis acids, such as TiCl₄, may afford avariety of products by increasing the formation of compounds (9), (10)or (11) in addition to compound (8). Since either of the compounds, (8),(9), (10) or (11), when reacted with base, may afford the desiredγ-carboline (12A), it may not be necessary to isolate or purify thegroup of compounds that resulted from the acid catalyzed cyclizationstep. Direct conversion from compound (7) to (12A) may achieve goodyields. When carbolone (8) is desired, scheme 4 may outline itssynthesis as well.

FIG. 5 shows possible intermediate steps to achieve the creation ofγ-carboline products as per preferred embodiments of the presentinvention described herein.

The following examples and preparations are provided solely for thepurpose of illustration and are not to be construed as limitations ofthe invention, many variations of which are possible without departingfrom the spirit or scope thereof.

EXAMPLE 1 Synthesis of 3-bromo-1-(tert-butyldimethylsilyl)indole (4)from indole (1)

Synthesis was performed according to a modified literature report ofBosch and co-workers as documented in J. Org. Chem., 1994, 59, 10-11. Toa solution of indole (4.00 g, 34.00 mmol) in 140 mL of THF at −78° C.was added dropwise a solution of n-BuLi (23.4 mL, 37.00 mmol, 1.6 Mhexane solution) in a two neck half-jacketed round-bottomed flaskequipped with a stir bar and a positive flow of nitrogen. Thetemperature was raised to −10° C. over a 15 minute period. After beingstirred at −10° C. for 30 minutes, the reaction mixture was cooled to−50° C. and a solution of TBDMSCl (5.80 g, 38 mmol) in 30 mL of THF wasadded. After the mixture was stirred at −10° C. for 3 hours, thetemperature was once again lowered to −78° C., and N-bromosuccinimide(6.00 g, 34 mmol) was added to the reaction mixture. The reactionmixture was stirred at −50° C. for 4 hours before the temperature wasallowed to rise slowly to room temperature. Hexane (100 mL) and pyridine(1 mL) were added, and the resulting suspension was removed byfiltration through a pad of Celite®. The filtrate was evaporated invacuo; however, extreme caution was taken not to heat the mixture above˜65° C., at which point decomposition occurred. The crude mixture waspurified by flash chromatography over silica gel using Hexane:CH₂Cl₂ ina 6:1 ratio affording 8.71 g (28.07 mmol) of the desired product, an 83%yield.

Preparation 1 Compounds (6a-j) from3-bromo-1-(tert-butyldimethylsilyl)indole (4)

To a stirred solution of 3-bromo-1-(tert-butyldimethylsilyl indole (4)(0.5 g, 1.6 mmol) in THF (15 mL), cooled to −78° C., was addeda-solution of t-BuLi (2.1 mL of a 1.7 M solution in pentane, 3.6 mmol).The mixture was allowed to stir for 15 minutes before the rapid additionof 1.1 equivalents of the corresponding tosylaldimine (2) (1.7 mmol) in30 mL of THF. The solution was allowed to stir at room temperature for12-18 hours. The reaction mixture was quenched with H₂O (30 mL) andextracted with CH₂Cl₂ (3×15 mL). The combined organic layer was washedwith H₂O (2×15 mL) and dried over MgSO₄. The resulting organic layer wasconcentrated to afford a brown, viscous oil. Purification using flashcolumn chromatography employing silica gel and a solvent system ofEtOAc:Hexanes (1:4) afforded the compounds (6a-j), respectively, inapproximately 50% yields.

Below illustrates the following afforded compounds (6a-j):

-   1.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-phenyl-methyl}-4-methyl-benzenesulfonamide    (6a): Mp=114-116° C. Elemental analysis calculated for    C₂₈H₃₄N₂O₂SSi: C, 68.53; H, 6.98; N, 5.71. Found: C, 68.22; H, 7.11;    N, 5.32.-   2.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-(4-methoxy-phenyl)-methyl}-4-methyl-benzenesulfonamide    (6b): Mp=155-156° C. Elemental analysis calculated for    C₂₉H₃₆N₂O₃SSi: C, 66.89; H, 6.97; N, 5.38. Found: C, 66.54; H, 6.67;    N, 5.01.-   3.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-(4-chloro-phenyl)-methyl}-4-methyl-benzenesulfonamide    (6c): Mp=135-137° C. Elemental analysis calculated for    C₂₈H₃₃ClN₂O₂SSi: C, 64.04; H, 6.33; N, 5.33. Found: C, 63.81; H,    6.13; N, 5.71.-   4.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-pyridin-2-yl-methyl}-4-methyl-benzenesulfonamide    (6d): Oil. Elemental analysis calculated for C₂₇H₃₃N₃O₂SSi: C,    65.95; H, 6.76; N, 8.55. Found: C, 65.63; H, 6.92; N, 8.81.-   5.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-(2-trifluoromethyl-phenyl)-methyl}-4-methyl-benzenesulfonamide    (6e): Mp=199-202° C. Elemental analysis calculated for    C₂₉H₃₃F₃N₂O₂SSi: C, 62.34; H, 5.95; N, 5.01. Found: C, 62.74; H,    6.12; N, 4.78.-   6.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-thiophen-2-yl-methyl}-4-methyl-benzenesulfonamide    (6f): Mp=152-154° C. Elemental analysis calculated for    C₂₆H₃₂N₂O₂S₂Si: C, 62.86; H, 6.49; N, 5.64. Found: C, 62.97; H,    6.21; N, 5.83.-   7.    N-{Anthracen-9-yl-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-3-yl]-methyl}-4-methyl-benzenesulfonamide    (6g): Mp=158-161° C. Elemental analysis calculated for    C₃₆H₃₈N₂O₂SSi: C, 73.18; H, 6.48; N, 4.74. Found: C, 72.89; H, 6.47;    N, 4.53.-   8.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-(2-nitro-phenyl)-methyl}-4-methyl-benzenesulfonamide    (6h): Mp=219-220° C. Elemental analysis calculated for    C₂₈H₃₃N₃O₄SSi: C, 62.77; H, 6.21; N, 7.84. Found: C, 62.54; H, 5.87;    N, 8.02.-   9.    N-{[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-furan-2-yl-methyl}-4-methyl-benzenesulfonamide    (6i): Semi-solid. Elemental analysis calculated for C₂₆H₃₂N₂O₃SSi:    C, 64.96; H, 6.71; N, 5.83. Found: C, 65.21; H, 6.58; N, 5.78.-   10.    N{N[1-(tert-Butyl-dimethyl-silanyl)-1H-indol-3-yl]-quinolin-2-yl-methyl}-4-methyl-benzenesulfonamide    (6j): Oil. Elemental analysis calculated for C₃₁H₃₅N₃O₂SSi: C,    68.72; H, 6.51; N, 7.76. Found: C, 69.03; H, 6.57; N, 7.94.

Preparation 2 Synthesis of Compounds (7a-g) from Compound 6

In a 50 mL round bottom flask was placed a sample of compound (6) (2.01mmol) dissolved in 30 mL of THF. This mixture was allowed to stir undera positive flow of N₂ for 15 minutes. Sodium ethoxide (2.21 mmol) wasadded to the stirred solution and stirring was continued for anadditional 30 minutes before adding ethyl bromoacetate (2.52 mmol). Theresulting solution was heated at reflux for 3.5 hours and allowed tocool slowly to room temperature before quenching with 10 mL of H₂O. Theresulting solution was extracted with CH₂Cl₂ (3×25 mL), washed with H₂O(3×15 mL) and dried over MgSO₄ before concentrating. The final traces ofsolvent were removed under vacuum for 12 hours. Gradient flash columnchromatography (hexane:ethyl acetate) was performed to afford theproduct.

The following compounds illustrate the various products generated fromthis procedure:

-   1.    [[[1-TBDMS-1H-indol-3-yl]-phenyl-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7a): A viscous red oil, 86% yield. Elemental    analysis calculated for C₃₂H₄₀N₂O₄SSi: C, 66.63; H, 6.99; N, 4.86.    Found: C, 66.28; H, 7.14; N, 4.61.-   2.    [[[1-TBDMS-1H-indol-3-yl]-(4-methoxy-phenyl)-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7b): A yellow powder, 72% yield. Mp=110-112.5° C.    Elemental analysis calculated for C₃₃H₄₂N₂O₅SSi: C, 65.31; H, 6.98;    N, 4.62. Found: C, 65.67; H, 7.03; N, 4.34.-   3.    [[[1-TBDMS-1H-indol-3-yl]-(4-chloro-phenyl)-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7c): A yellow oil, 63% yield. Elemental analysis    calculated for C₃₂H₃₉ClN₂O₄SSi: C, 62.88; H, 6.43; N, 4.58. Found:    C, 62.55; H, 6.22; N, 4.88.-   4.    [[[1-TBDMS-1H-indol-3-yl]-pyridin-2-yl-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7d): A yellow powder, 61% yield. Mp=87.5-93° C.    Elemental analysis calculated for C₃₁H₃₉N₃O₄SSi: C, 64.44; H, 6.80;    N, 7.27. Found: C, 64.13; H, 7.12; N, 6.93.-   5.    [[[1-TBDMS-1H-indol-3-yl]-(2-trifluoromethyl-phenyl)-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7e): A yellow oil, 59% yield. Elemental analysis    calculated for C₃₃H₃₉F₃N₂O₄SSi: C, 61.47; H, 6.10; N, 4.34. Found:    C, 61.14; H, 5.86; N, 3.97.-   6.    [[[1-TBDMS-1H-indol-3-yl]-thiophen-2-yl-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7f): A brown powder, 43% yield. Mp=87.5-93° C.    Elemental analysis calculated for C₃₀H₃₈N₂O₄S₂Si: C, 61.82; H, 6.57;    N, 4.81. Found: C, 61.71; H, 6.32; N, 5.18.-   7.    [[Anthracen-9-yl-[1-TBDMS-1H-indol-3-yl]-methyl]-(toluene-4-sulfonyl)-amino]-acetic    acid ethyl ester (7g): A yellow oil, 61% yield. Elemental analysis    calculated for C₄₀H₄₄N₂O₄SSi: C, 70.97; H, 6.55; N, 4.14. Found: C,    71.36; H, 6.46; N, 3.83.

Preparation 3 Synthesis of Compound (8) from Compound (7)

Into a 50 mL round bottom flask a sample of compound (7) (8.42 mmol) wasdissolved in 25 mL of THF. The solution was allowed to stir under apositive flow of N₂ for 15 minutes. To the stirred solution was added1.00 g of Bentonite K-10 clay. The resulting solution was heated in an80° C. oil bath for 12 hours. Upon completion, the reaction mixture wascooled, then diluted with 20 mL CH₂Cl₂ and vacuum filtered with the aidof a Büchner funnel to remove the clay from the reaction mixture. Theorganic layer was dried over MgSO₄ and concentrated under reducedpressure. Final traces of solvent were removed under vacuum 4 hr.Gradient flash column chromatography (hexane:ethyl acetate) wasperformed to afford the desired product (8).

The following compounds illustrate the various solutions from thispreparation:

-   1.    1-Phenyl-2-(toluene-4-sulfonyl)-1,2,3,5-tetrahydro-pyrido[4,3-b]indol-4-one    (8a): 61%. Elemental analysis calculated for C₂₄H₂₀N₂O₃S: C, 69.21;    H, 4.84; N. 6.73. Found: C, 68.97; H, 5.13; N, 6.49.-   2.    1-(4-Methoxy-phenyl)-2-(toluene-4-sulfonyl)-1,2,3,5-tetrahydro-pyrido[4,3-b]indol-4-one    (8b): Dark oil, 45% yield (6 mg, 0.01 mmol). Elemental analysis    calculated for C₂₅H₂₂N₂O₄S: C, 67.25; H, 4.97; N, 6.27. Found: C,    67.04; H, 5.16; N, 6.19.-   3.    1-(4-Chloro-phenyl)-2-(toluene-4-sulfonyl)-1,2,3,5-tetrahydro-pyrido[4,3-b]indol-4-one    (8c): 57%. Elemental analysis calculated for C₂₄H₁₉ClN₂O₃S: C,    63.92; H, 4.25; N, 6.21. Found: C, 64.01; H, 4.52; N, 5.93.

Preparation 4 Synthesis of Compound (11) from Compound (7)

Into a 50 mL round bottom flask a sample of compound (7) (8.42 mmol) wasdissolved in 25 mL of THF. The solution was allowed to stir under apositive flow of N₂ for 15 minutes. To the stirred solution was added1.00 g of Bentonite K-10 clay. The resulting solution was heated in an80° C. oil bath for 12 hours. The reaction was cooled, vacuum filteredwith the aid of a Büchner funnel to remove the clay from the reactionmixture. To the resulting combined organic layer was added 20 mL THF,NaOH (16.84 mmol) and tetrabutylammonium bromide (0.84 mmol). Thesolution was heated at reflux for 6 hours, allowed to slowly cool toroom temperature, diluted with 20 mL CH₂Cl₂ and neutralized with 1M HCl.The resulting solution was washed with H₂O (3×20 mL) and Brine (1×15mL). The organic layer was dried over MgSO₄ and concentrated underreduced pressure. Final traces of solvent were removed under vacuum for4 hours. Gradient flash column chromatography (hexane:ethyl acetate) wasperformed to afford the desired product (11).

The following compounds illustrate the various products generated fromthis procedure:

-   1. 1-Phenyl-5H-pyrido[4,3-b]indol-4-ol (11a): A yellow oil, 35%    yield (from compound (7)). Elemental analysis calculated for    C₁₇H₁₂N₂O: C, 78.44; H, 4.65; N, 10.76. Found: C, 78.21; H, 4.58; N;    10.43.-   2. 1-(4-Methoxy-phenyl)-5H-pyrido[4,3-b]indol-4-ol (11b): A yellow    oil, 31% yield (from compound (7)). Elemental analysis calculated    for C₁₈H₁₄N₂O₂: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.09; H,    4.75; N, 9.51.-   3. 1-(4-Chloro-phenyl)-5H-pyrido[4,3-b]indol-4-ol (11c): A yellow    oil, 28% yield (from compound (7)). Elemental analysis calculated    for C₁₇H₁₁ClN₂O: C, 69.28; H, 3.76; N, 9.50. Found: C, 68.93; H,    3.54; N, 9.79.-   4. 1-Pyridin-2-yl-5H-pyrido[4,3-b]indol-4-ol (11d): A brown oil, 33%    yield (from compound (7)). Elemental analysis calculated for    C₁₆H₁₁N₃O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.39; H, 4.08; N,    15.99.-   5. 1-(2-Trifluoromethyl-phenyl)-5H-pyrido[4,3-b]indol-4-ol (11e): A    yellow oil, 43% yield (from compound (7)). Elemental analysis    calculated for Cl₁₈H₁₁F₃N₂O: C, 65.85; H, 3.38; N, 8.53. Found: C,    66.02; H, 3.57; N, 8.46.-   6. 1-Thiophen-2-yl-5H-pyrido[4,3-b]indol-4-ol (11f): A yellow oil,    18% yield (from compound (7)). Elemental analysis calculated for    C₁₅H₁₀N₂OS: C, 67.65; H, 3.78; N, 10.52. Found: C, 67.78; H, 3.69;    N, 10.35.-   7. 1-Anthracen-9-yl-5H-pyrido[4,3-b]indol-4-ol (11g): An orange oil,    26% yield (from compound (7)). Elemental analysis calculated for    C₂₅H₁₆N₂O: C, 83.31; H, 4.47; N, 7.77. Found: C, 83.58; H. 4.63; N,    8.06.

Preparation 5 Synthesis of Compound (12) from Compound (8)

Compound (8) was dissolved in 25 mL of THF and allowed to stir for 15minutes before the addition of NaOH (16.84 mmol) and tetrabutylammoniumbromide (0.84 mmol). The resulting solution was heated at reflux for 6hours and then allowed to slowly cool to room temperature, diluted with20 mL CH₂Cl₂ and neutralized with 1M HCl. The resulting solution waswashed with H₂O (3×20 mL) and brine (1×15 mL). The organic layer wasdried over MgSO₄ and concentrated under reduced pressure. Final tracesof solvent may be removed under vacuum for 4 hours. Gradient flashcolumn chromatography (hexane:ethyl acetate) may be performed to affordthe desired product (11).

The foregoing descriptions of the preferred embodiments of the presentinvention have been presented for purposes of illustration anddescription. They are not intended to be exhaustive or to limit theinvention to the precise forms disclosed, and obviously manymodifications and variations are possible in light of the aboveteaching. For example, THF could be substituted with other organicsolvents such as ethers, esters, or amides. The illustrated embodimentswere chosen and described in order to best explain the principles of theinvention and its practical application to thereby enable others skilledin the art to best utilize the invention in various embodiments and withvarious modifications as are suited to the particular use contemplated.Any reference to claim elements in the singular, e.g. using the articles“a,” “an,” “the,” or “said” is not construed as limiting the element tothe singular.

1. A compound of formula:

or a prodrug or salt thereof.
 2. A compound according to claim 1 whereinR is a hydroxyl.
 3. A compound according to claim 1 wherein R is analkyl.
 4. A compound according to claim 1 wherein R is a hydrogen.
 5. Acompound according to claim 1 wherein R is an alkoxyl.
 6. A compoundaccording to claim 1 wherein R is an alkenyl.
 7. A compound according toclaim 1 wherein Ar is an aryl.
 8. A compound according to claim 1wherein Ar is a substituted aryl.
 9. The compound according to claim 1,wherein the composition is adapted for the treatment ofneurodegenerative disease or neuronal damage.
 10. The compound accordingto claim 1, wherein the composition is adapted for use as anantipsychotic pharmaceutical.
 11. The compound according to claim 1,wherein the composition is adapted for use as an antibioticpharmaceutical.
 12. The compound according to claim 1, wherein thecomposition is adapted for use as an antitumor pharmaceutical.
 13. Acompound of formula:

or a prodrug or salt thereof.
 14. A compound according to claim 13wherein R¹ is a Ts.
 15. A compound according to claim 13 wherein R¹ is aHydrogen.
 16. A compound according to claim 13 wherein R² is a Hydrogen.17. A compound according to claim 13 wherein R² is a TBDMS.
 18. Thecompound according to claim 13, wherein the composition is adapted forthe treatment of neurodegenerative disease or neuronal damage.
 19. Thecompound according to claim 13, wherein the composition is adapted foruse as an antipsychotic pharmaceutical.
 20. The compound according toclaim 13, wherein the composition is adapted for use as an antibioticpharmaceutical.
 21. The compound according to claim 13, wherein thecomposition is adapted for use as an antitumor pharmaceutical.